An Audit of Lamotrigine, Levetiracetam and Topiramate Usage for Epilepsy in a District General Hospital

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provided by Elsevier - Publisher Connector Seizure (2005) 14, 422—428

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An audit of lamotrigine, levetiracetam and topiramate usage for epilepsy in a district general hospital

Brian Chappell *, Pamela Crawford

Department of Neurosciences, York District Hospital, Wigginton Road, York YO31 8HE, UK

KEYWORDS Summary The aim of this audit was to ascertain outcomes for people who had taken Audit; or who were still taking three ‘‘new generation’’ broad-spectrum antiepileptic drugs Anti-epileptic drugs; (AEDs), namely lamotrigine, levetiracetam and topiramate. Seizures; Thirteen percent of people became seizure free and approximately, one-third had Outpatients a reduction of greater than 50% in their seizures. Two-thirdsof people were still taking their audit AED. In addition, approximately one-third of people with a learning disability derived substantial beneﬁt, although the rate of seizure freedom was lower. All three AEDs were most successful at treating primary generalised epilepsy and least successful with symptomatic generalised epilepsy. With some reservations the data suggests that levetiracetam and topiramate are the most efﬁcacious AEDs, but topiramate is the least well tolerated. These results mean consideration of a ‘‘general prescribing policy’’ is important when using and choosing these AEDs. We conclude that lamotrigine, levetiracetam and topiramate are useful additions to the armamentarium of AEDs. # 2005 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.

Introduction mate, which are the most commonly prescribed ‘‘new generation’’AEDs in the United Kingdom.4 They For many years, physicians had few choices for treat- were chosen because they are all ‘‘broad spectrum’’, ing epileptic seizures. Within the past 15 years, many in other words they are known to have some effect on ‘‘new generation’’ antiepileptic drugs (AEDs) have the vast majority of seizure types. Most clinical trials been introduced. The new agents have been shown in of these AEDs initially investigated their efficacy for clinical trials to offer similar efficacy compared with localisation-related seizures with or without second- 5—10 older, more established AEDs.1,2 Some studies have ary generalisation. There is trial data for lamo- shown that the new agents offer important improve- trigine and topiramate in primary generalised 11—14 ments in safety and side effect profile.1,3 epilepsy, but as yet the data for levetiracetam 15,16 The three ‘‘new generation’’ AEDs studied in this is mainly from experience in clinical practice. audit are lamotrigine, levetiracetam and topira- This means the former two AEDs have wider licences than the latter. Nevertheless, this study reports on * Corresponding author. Tel.: +44 1484 647895. usage of all three AEDs in a wide range of seizure E-mail address: [email protected] (B. Chappell). types.

The present data available on usage of these three When seizures started, 372 (80%) of the people AEDs in everyday adult UK district hospital clinical exposed were aged 20 years and under, 94 (20%) practice is limited.16—24 It is, therefore, important were 21—65 years old inclusive and 0 (0%) were 66 that knowledge is expanded of their usage in a ‘‘gen- years and over. eral’’ epilepsy population, as the results are likely to Ninety-three exposures (20%) were in people who be different from the trial data. This study aims to had primary generalised epilepsy, 57 (12%) had contribute to the expansion of this knowledge base. symptomatic generalised epilepsy and 317 (68%) had localisation-related epilepsy. When audited 245 (52%) were taking lamotrigine Methods (LTG), 94 (20%) were taking topiramate (TPM) and 129 (28%) were taking levetiracetam (LEV). Hospital patient notes were searched on three sepa- The following were the doses attained for each of rate occasions for people who were taking or who the audit AEDs: had taken one of the three audit AEDs. The same search critieria were used on each occasion. In the AED Minimum Maximum Mean Standard Results section we, therefore, refer to the number deviation of exposures to the audit AEDs as opposed to the Lamotrigine 25 1000 291 178.2430 number of people. Topiramate 25 900 349 218.8819 The three patient note searches were undertaken Levetiracetam 500 4000 1994 690.6640 approximately 2 years post the United Kingdom licensing of each audit AED. Lamotrigine was, there- Ninety-six exposures (20%) were in people who fore, audited ﬁrst, topiramate second and levetir- had learning disabilities. acetam third. Some of the cohort had been taking The following bar chart shows the number of AEDs their audit AED much longer than 2 years, because people were already taking when their audit AED they were initiated on a particular AED pre-licence. was added (Bar Chart 1). Some people have taken more than one of the This second chart shows the number of AEDs the audit AEDs and will, therefore, be counted in the person had already taken at sometime before the data on more than one occasion. introduction of the audit AED (Bar Chart 2). The following categories of information were recorded: audit drug, dose attained on audit drug, name, hospital number, sex, age, age of seizure Cohort characteristics and each drug onset, whether the person had learning disabilities, audited (N = 468) whether the person had primary generalised, symptomatic generalised or a localisation-related onset To try and ascertain whether the exposures to each epilepsy,outcome for seizure frequency compared to audit AED were fairly similar, all exposures were baseline, side effects, whether the person is continu- compared for their basic characteristics against the ing on the audit AED and if not the length of time drug they were taking at the point of audit. before the person stopped taking the audit AED. The groups were similar in the case of age, sex, Results were recorded in both EXCEL and SPSS age of onset, symptomatic generalised epilepsy, 11.0 for Windows. Analysis was completed using SPSS. Where groups of people were compared for signiﬁcance the statistical test used was chi-square with one exception, for ‘‘time to drop out’’ the Kaplan—Meier test was used.

Results

Characteristics of the exposures to an audit AED

Two hundred and ten exposures (45%) were in males and 258 (55%) were in females. Sixty-three (14%) exposures were in those aged 20 years and under, 397 (85%) were 21—65 years old inclusive and 8 (2%) were 66 years and over. Chart 1 424 B. Chappell, P. Crawford

Table 1 Drug efficacy (N = 451). Seizure Number Percent Valid Cumulative frequency percent percent Seizure free 58 12.4 12.9 12.9 >50% 92 19.7 20.4 33.3 decrease 1—50% 159 34.0 35.3 68.5 decrease No efficacy 136 29.1 30.2 98.7 Seizures 6 1.3 1.3 100.0 worse Total 451 96.4 100.0 Missing 17 3.6 Chart 2 system localisation-related epilepsy and the number with a Total 468 100.0 learning disability. There was significant difference between each comparing the topiramate and levetiracetam exposure group in that those with primary general- groups. In the case of ‘‘AEDTAKE’’ the topiramate ised epilepsy were more likely to be prescribed leve- group were taking less other AEDs when it was tiracetam ( p < .029). There were also significant added ( p < .001), but for ‘‘AEDPRIOR’’ the levetir- differences in the number of AEDs exposed people acetam group had tried less other AEDs before it were already taking when the audit AED was added was introduced ( p < .040). (Bar Chart 1) and the number of AEDs exposed people had already taken at sometime before the introduc- Drug efficacy (N = 451) tion of the audit AED (Bar Chart 2). The latter two pieces of data suggested that Table 1 outlines the seizure outcome for 451 of the the lamotrigine group possibly had less severe exposures, using commonly agreed markers. Sei- epilepsy. For ‘‘AEDTAKE’’ the lamotrigine group zure-free is defined as no seizures for 6 months or were taking less other AEDs when it was added longer. than the topiramate group ( p < .001) and the levetiracetam group ( p < .001). This was also People exposures continuing on an audit drug thecasefor‘‘AEDPRIOR’’ where the lamotrigine (N = 468) group had taken less other AEDs before it was Three hundred and twelve (67%) were continuing on introduced: topiramate ( p < .001); levetiracetam their audit drug and 156 (33%) were not, due to ( p < .001). The picture was much less clear when either a lack of efficacy or side effect problems.

Table 2 Time to ‘‘drop-out’’ (N = 155). Time Number Percent Valid percent Cumulative percent <3 month 25 16.0 16.1 16.1 4—6 months 66 42.3 42.6 58.7 7—12 months 29 18.6 18.7 77.4 13—24 months 16 10.3 10.3 87.7 >24 months 19 12.2 12.3 100.0 Total 155 99.4 100.0 Missing system 1 0.6 Total 156 100.0

Table 3 Primary generalised epilepsy (N = 88). Seizure-free >50% decrease 1—50% decrease No efﬁcacy Seizures worse Total Number 17 19 29 22 1 88 Percentage within (%) 19.3 21.6 33.0 25.0 1.1 100.0 An audit of lamotrigine, levetiracetam and topiramate usage 425

Table 4 Symptomatic generalised epilepsy (N = 56). Seizure-free >50% decrease 1—50% decrease No efﬁcacy Seizures worse Total Number 5 13 20 16 2 56 Percentage within (%) 8.9 23.2 35.7 28.6 3.6 100.0

Table 5 Localisation-related epilepsies (N = 306). Seizure-free >50% decrease 1—50% decrease No efﬁcacy Seizures worse Total Number 36 58 110 99 3 306 Percentage within (%) 11.8 19.0 35.9 32.4 1.0 100.0

Time to ‘‘drop-out’’ (N = 155) free. In the case of localisation-related epilepsy, the In the case of the exposures where an audit drug had figure was eight out of 80 (10%) for those becoming been stopped, Table 2 outlines the length of time it seizure-free and for symptomatic generalised epi- took for this to occur. lepsy, zero out of 12 (0%). Drug efficacy and epilepsy type Comparison of drug efficacy Tables 3—5 outline seizure outcome for the three chosen categories. Table 6 outlines the efficacy of each audit AED. Levetiracetam efficacy and epilepsy type (N = 126) Comparison of ‘‘drop-out’’

For exposures in people who had primary general- Table 7 outlines how many of the exposures are still ised epilepsy six out of 35 (17%) became seizure- taking their audit AED or not.

Table 6 Lamotrigine (LTG) vs. levetiracetam (LEV) vs. topiramate (TPM) (N = 451). AED Seizure-free >50% decrease 1—50% decrease No efﬁcacy Seizures worse Total Lamotrigine Number 24 40 65 100 6 235 % within 10.2 17.0 27.7 42.6 2.6 100.0 Topiramate Number 20 12 51 7 0 90 % within 22.2 13.3 56.7 7.8 0.0 100.0 Levetiracetam Number 14 40 43 29 0 126 % within 11.1 31.7 34.1 23.0 0.0 100.0 Total Number 58 92 159 136 6 451 % within 12.9 20.4 35.3 30.2 1.3 100.0

Value d.f. Asymp. sig. (two-sided) Chi-square tests: lamotrigine (LTG) vs. levetiracetam (LEV) Pearson chi-square 21.213 4 0.000 Value d.f. Asymp. sig. (two-sided) Chi-square tests: lamotrigine (LTG) vs. topiramate (TPM) Pearson chi-square 49.029 4 0.000

Value d.f. Asymp. sig. (two-sided) Chi-square tests: levetiracetam (LEV) vs. topiramate (TPM) Pearson chi-square 24.954 3 0.000 Comparison of drug efﬁcacy. 426 B. Chappell, P. Crawford

Comparison of time to ‘‘drop out’’ (N = 155) Table 7 Lamotrigine (LTG) vs. levetiracetam (LEV) vs. topiramate (TPM) (N = 468). The following is a Kaplan—Meier graph comparing the drop-out time of the three audit AEDs. AED Continuing Not continuing Total Lamotrigine Number 160 85 245 % within 65.3% 34.7% 100.0% Topiramate Number 45 49 94 % within 47.9% 52.1% 100.0% Levetiracetam Number 107 22 129 % within 82.9% 17.1% 100.0% Total Number 312 156 468 % within 66.7% 33.3% 100.0%

Value d.f. Asymp. sig. (two-sided) Chi-square tests: lamotrigine (LTG) vs. levetiracetam Exposures in those people with learning (LEV) disabilities (LDs) Pearson 12.874 1 0.000 chi-square Table 8 outlines the seizure outcome using com- Value d.f. Asymp. sig. (two-sided) monly agreed markers. Chi-square tests: lamotrigine (LTG) vs. topiramate Table 9 outlines the number still taking their (TPM) audit AED. Pearson 8.638 1 0.003 chi-square Discussion Value d.f. Asymp. sig. (two-sided) Chi-square tests: levetiracetam (LEV) vs. topiramate This is one of the largest cohorts of people with (TPM) epilepsy taking a new generation antiepileptic Pearson 30.823 1 0.000 reported from a United Kingdom district general chi-square hospital. The cohort is not strictly similar to those Comparison of ‘‘drop-out’’. usually found in neurosciences outpatients as the

Table 8 Efﬁcacy of AEDs in those with LDs. Seizure frequency Number Percent Valid percent Cumulative percent Seizure-free 5 5.2 5.3 5.3 >50% decrease 28 29.2 29.5 34.7 1—50% decrease 35 36.5 36.8 71.6 No efﬁcacy 24 25.0 25.3 96.8 Seizures worse 3 3.1 3.2 100.0 Total 95 99.0 100.0 Missing system 1 1.0 Total 96 100.0

Table 9 Number of people with LDs continuing to take their audit AED. Frequency Percent Valid percent Cumulative percent Continuing 71 74.0 74.0 74.0 Not continuing 25 26.0 26.0 100.0 Total 96 100.0 100.0 An audit of lamotrigine, levetiracetam and topiramate usage 427 main consultant has a special interest in epilepsy and fering seizure types. This is not the case for levetir- is involved with both a joint learning disability clinic acetam. Data from this study would suggest that and antiepileptic drug trials. This means that the levetiracetam has a wide spectrum of activity, being cohort is biased towards the more severe epilepsies probably as efficacious for primary generalised epi- in comparison to a standard neurosciences outpatient lepsy (17% seizure-free) as it is for localisation- population. It is probably, therefore, logical to sug- related epilepsy (10% seizure-free) in a population gest that the outcomes identified may be improved previously resistant to treatment. upon in general neurosciences outpatient clinics. The cohort contained 96 exposures to an audit The efficacy and usefulness of new generation AED in those with learning disabilities. People with antiepileptics has been challenged by some22 and learning disabilities are usually more resistant to supported by others.1,15,16,25 This data would sug- treatment than others31 and this study confirmed gest a useful role for lamotrigine, topiramate and this. Only 5% of the exposures in this group led to levetiracetam. Thirteen percent of the exposures to seizure freedom against 13% of those who did not an audit AED led to seizure freedom and 33% led to a have learning disabilities. However, very interest- greater than 50% decrease. Sixty-seven percent of ingly, when you group together exposures that the exposures were continuing to take their audit became seizure-free and those with a greater than drug, which virtually balances with the figure of 69% 50% decrease in seizures, people with learning dis- of the exposures that had some sort of seizure abilities responded in a similar way; 35% exposure decrease, however, small. If people did stop taking responders against 33%. This latter finding deserves their audit drug, unsurprisingly, they were most more investigation and further research. likely to do this in the first 6 months (nearly 60% and nearly 90% within 12 months). This study chose to have a simple regime for Conclusion classifying epilepsy type: primary generalised, symptomatic generalised and localisation related. The As 13% of the people exposures led to seizure free- three audit drugs were much more likely to success- dom and approximately one-third had a reduction of fully treat primary generalised epilepsy. As yet, leve- greater than 50% in their seizures in this study, the tiracetam does not have a licence for treating this conclusion has to be that lamotrigine, levetiracetam type of epilepsy, but this data suggests it is useful. and topiramate are useful additions to the arma- With this type of audit data, it is not generally mentarium of AEDs in a ‘‘general’’ population with advisable to try and compare outcomes for the three epilepsy. Approximately, one-third of the exposures audit drugs. There are a number of reasons for this, in people with a learning disability also had a sub- not least that by definition the group being treated stantial benefit, although the rate of seizure free- becomes more ‘‘resistant’’ to treatment with time, dom was lower. i.e., many people in the levetiracetam group have All three AEDs are most successful at treating probably already been ‘‘resistant’’ to firstly lamo- primary generalised epilepsy and least successful trigine and secondly topiramate before they receive with symptomatic generalised epilepsy. levetiracetam. For most of the core data (e.g. age, With some reservations the data suggests that sex, etc.) the three groups were similar, but people topiramate is the most efficacious AED, followed by were more likely to have primary generalised epi- levetiracetam, but the least well tolerated. These lepsy in the levetiracetam group. 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